Extensive research has been focused on agents that relieve pain and on their preparation. Interest has recently developed in compounds that display antagonistic activity against narcotic drugs, mainly for two reasons. First, it is desirable to have narcotic antagonist compounds which give rise to analgesia while at the same time having a greatly reduced abuse potential. Secondly, it is desirable to have compounds that are useful in the treatment of narcotic addiction. N-allylnorcodeine is probably the first specific narcotic antagonist prepared and studied. It was synthesized by J. Pohl in 1914. Several similar compounds have been synthesized in an effort to prepare a long-acting orally effective antagonist. In general, all of these compounds are characterized by a relatively short duration of action, low oral effectiveness, and varying degrees of agonistic effects.
Several compounds of the piperidine class have been found to display interesting analogesic activity, and some have displayed varying degrees of antagonist activity, as described for example by Nurimoto and Hayashi, Japan J. Pharmcol. 23 743 (1973). Many 1,2,3-trialkyl-3-arylpiperidines have been prepared and evaluated as analogesic drugs; see for example U.S. Pat. Nos. 3,043,845 and 2,892,842. Very interesting antagonistic properties have been displayed by a group of 1,4-disubstituted-4-arylpiperidines, as described by Langbein, et al., Narcotic Antagonists, Advances in Biochemical Psynchopharmacology, Vol. 8, Raven Press, New York, 1974, pp. 157-165. Several 1-methyl-4-alkyl-4-(3-hydroxyphenyl)piperidines were prepared and evaluated as analogesics by McElvain, U.S. Pat. No. 2,892,842.
Very little work has been directed to the preparation of 1,3,4trisubstituted-4-arylpiperidines, presumably because of the difficulty of their preparation. McElvain et al. reported the preparation of 1,3,4trimethyl-4-(2-methoxyphenyl)piperidine as a biproduct in the synthesis of a 1,4-dialkyl-4-arylpiperidine; J. Am. Chem. Soc. 80, 3915 (1958). It was reported, however, that an ortho- or paramethoxyl group on the phenyl substituent rendered such compounds almost totally inactive as analgesics. Similarly, Janssen prepared several 1-aroyl-3,4-dialkyl-4-arylpiperidine derivatives which are useful as central nervous system depressants, U.S. Pat. No. 3,080,372.
It is an object of this invention to provide a process for preparing 4-arylpiperidines substituted in the 1, 3, and 4-positions with alkyl or alkenyl groups. It is a further object to provide such piperidines which display useful analgesic activity and which, in some cases, are potent narcotic antagonists. An additional object of the invention is to provide novel intermediates useful for preparing new piperidines.